A GABA Pathway to Faster Acting Antidepressants

描述（由申请人提供）：越来越多的临床前和临床证据表明，gaba能缺陷是重度抑郁症（MDD）的一个重要因素。然而，这些缺陷存在的神经元回路和调节抑郁样行为的个体GABAA受体亚型尚不清楚。通过分析啮齿类动物对慢性社会失败应激的反应，我们提出研究a2-和a3- GABAA受体在特定神经回路中如何在从“正常”状态到“下降”（即抑郁）状态的行为转变中发挥作用。使用一种新的遗传药理学方法，我们将进一步评估在社交失败期间给予高度a2特异性[或a3特异性]激动剂是否可以防止[或促进]从“正常”状态过渡到“下降”状态。我们还将评估这种激动剂是否能在慢性社会失败停止后迅速促进[或阻止]从抑郁状态向正常状态的转变。拟议的研究有望证明a2特异性激动作用产生急性抗抑郁样作用，并将为开发一类新型抗抑郁药物提供概念证明。

DESCRIPTION (provided by applicant): There is converging preclinical and clinical evidence that GABAergic deficits are an important factor in major depressive disorders (MDD). However, the neuronal circuits in which these deficits exist and the individual GABAA receptor subtypes that modulate depressive-like behavior are unknown. By analyzing the response to chronic social defeat stress, a rodent model of depression with construct, face, and predictive validity, we propose to study how a2- and a3-containing GABAA receptors in defined neuronal circuits play a role in the behavioral transition from a "normal" state to a "down" (i.e. depressed) state and vice versa. Using a novel genetic-pharmacological approach we will further assess whether a highly a2- specific [or a3-specific] agonist administered during social defeat can prevent [or promote] the transition from the "normal" state to the "down" state. We will also assess whether such an agonist can acutely promote [or prevent] the transition from the depressed state back to the normal state when administered after cessation of chronic social defeat. The proposed studies are expected to demonstrate that a2-specific agonism generates an acute antidepressant-like effect and will provide proof-of-concept for the development of a novel class of antidepressant agents.